tbuckley/cabot-search huggingface dataset:
Abstract SY19-01: Investigating cancer determinants of tumor immune composition
Authors: Brian Brown
Journal: Cancer Research (2022)

Abstract The cellular composition, spatial architecture, and tissue localization of a tumor have a major impact on a cancer’s progression and response to therapy. These factors are particularly relevant to tumor immunity as immune cell composition and localization within the tumor microenvironment (TME) is one of the major determinants of response to immunotherapy and patient outcome. Spatially resolved single cell genome sequencing has revealed that many genetically distinct sub-clones exist in proximity in tumors and can have different TME compositions, but how specific genes influence the TME, or how neighboring clones influence one another is not well-defined. Indeed, while some genes involved in orchestrating the TME have been identified, the potential roles of many genes in influencing the architecture and immune composition of different tumors are not established. To enable scale up studies to identify determinants of TME biology and tumor immunity, we established a first-of-its-kind in vivo spatial functional genomics platform called Perturb-map. We applied Perturb-map to knockout (KO) dozens of genes in parallel in a mouse model of lung cancer and simultaneously assessed how each KO influenced tumor growth, histopathology, and immune composition. Additionally, we paired Perturb-map and spatial transcriptomics for unbiased analysis of CRISPR-edited tumors. In contrast to in vitro CRISPR screens, we found KO of positive regulators of IFNγ signaling led to a major reduction of tumor burden, with varying impact from different pathway components. KO of Socs1, a negative regulator of IFNγ signaling, provided a growth advantage though was accompanied by increased T cell infiltration and notably, Socs1 KO tumors were more responsive to PDL1 blockade. Perturb-map also found that KO of the TGFβ Receptor 2 (Tgfbr2) resulted in a growth advantage, but unlike Socs1 KO, T cells were excluded from the lesions and the TME converted to a fibro-mucinous state. Spatial transcriptomics revealed TGFβ signaling was upregulated in Tgfbr2 KO tumors. Further analysis indicated this signal was from TGFβ-mediated activation of fibroblasts in tumors where cancer cells lost Tgfbr2, suggesting the mechanism for TME remodeling and T cell exclusion in Tgfbr2 KO tumors. These studies establish Perturb-map for functional genomics within tissue at single cell-resolution with spatial architecture preserved and provide insight into how TGFβ responsiveness of cancer cells can affect the TME (Dhainaut, Rose et al. BioRxiv 2021, doi.org/10.1101/2021.07.13.451021). Citation Format: Brian Brown. Investigating cancer determinants of tumor immune composition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY19-01.
Abstract 3200: Examining the role of obesity and leptin signaling in triple negative breast cancer
Authors: Courtney Brock, Maryl Wright, Khoa Nguyen, Katherine Hebert, Madlin Alzoubi, Thomas Cheng, Bridgette Collins-Burow, Matthew Burow
Journal: Cancer Research (2022)

Abstract Individuals with a high body mass index (BMI) have an increased risk of developing many adult cancers, including breast cancer. In triple negative breast cancer (TNBC), a clinically aggressive subtype of breast cancer, increased BMI is associated with more aggressive tumor types and a higher risk of recurrence. The differences in outcomes between obese and non-obese breast cancer patients is a consequence of the complex interplay between social, environmental, and physiological factors that contribute to the etiology of breast cancer. Therefore, understanding the complex signaling events in the obese tumor microenvironment is essential. Adipose stem cells (ASCs) are a component of the breast microenvironment, and are a subset of mesenchymal stem cells. ASCs from obese patients (obASCs) secrete higher levels various cytokines and adipokines that induce a more invasive phenotype in triple negative breast cancer cells compared to ASCs from lean individuals. Leptin, an adipokine that is expressed proportionally to fat mass, has been implicated in many cancers. Increased leptin and leptin receptor expression is associated with worse prognosis. This study seeks to examine the role of leptin signaling in triple negative breast cancer. Previous work in conjunction with a collaborating lab has shown that leptin signaling promotes metastasis and increased expression of epithelial-mesenchymal transition (EMT) markers in triple negative breast cancer. This project expands upon this work through using both patient-derived cell lines and and patient-derived xenografts (PDX), and examines the role of leptin signaling both in vitro and in vivo. To determine the effects of obesity upon a PDX model, a high fat diet was used to induce obesity in vivo. Exposure to conditioned media harvested from obASCs increased the percentage of TNBC cells that expressed cancer stem cell markers, whereas exposure to a small peptide antagonist of the leptin receptor decreased the percentage of cells with CSC markers. PDX tumors implanted into diet-induced obesity mice had an increased volume compared to tumors implanted into lean controls. Conclusions: These molecular differences may contribute to the differences in cancer outcomes between obese and lean individuals with breast cancer, and further study of the crosstalk between obASCs and TNBC is critical. Citation Format: Courtney Brock, Maryl Wright, Khoa Nguyen, Katherine Hebert, Madlin Alzoubi, Thomas Cheng, Bridgette Collins-Burow, Matthew Burow. Examining the role of obesity and leptin signaling in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3200.
A biological classification of Huntington's disease: the Integrated Staging System
Authors: Sarah J Tabrizi, Scott Schobel, Emily C Gantman, Alexandra Mansbach, Beth Borowsky, Pavlina Konstantinova, Tiago A Mestre, Jennifer Panagoulias, Christopher A Ross, Maurice Zauderer, Ariana P Mullin, Klaus Romero, Sudhir Sivakumaran, Emily C Turner, Jeffrey D Long, Cristina Sampaio
Journal: The Lancet Neurology (2022)
Abstract 281: Culture of circulating tumor cells isolated from cancer patients with metastatic disease
Authors: Nikhila Reddy Sultanpuram, Isaiah Kim, Hossein Sendi, Nicole Kanpe, Tilden Hagen, Kyle Wagner, Andrew Wang
Journal: Cancer Research (2022)

Abstract OBJECTIVE: The purpose of this study is to investigate the feasibility of using decellularized tissue ECM to culture circulating tumor cells (CTCs) collected from patients with metastatic solid tumor malignancies. BACKGROUND: Circulating tumor cells (CTCs) have been shown to recapitulate the heterogeneity and biology of patients’ cancers. However, there is a lack of technologies that can culture patient CTCs. Our group has previously shown that tumor cells cultured on decellularized tissue closely mimic the in vivo condition. Therefore, we hypothesized that we can utilized decellularized tissue as strata to culture CTCs. METHODS: Peripheral blood samples were collected from patients with metastatic disease who had not received any systemic therapy in the last six months or are progressing on systemic therapy. PMBC layer, which contains lymphocytes, monocytes, dendritic cells and CTCs (in metastatic patients) is separated from whole blood by Ficoll gradient. The cells are then mixed with decellularized lung or liver material and cultured using stemcell media. RESULTS: 26 subjects were enrolled in this study. We were able to generate cell colonies from 12 patients’ samples (either colonies on liver or lung strata). Of the patient samples that did not develop tumor colonies, 9/14 subjects had no metastatic tumors in either lung or liver. Colonies from the cultures were characterized by histological staining and SEM imaging. Of the samples that the tumor colonies were large enough for H&amp;E, we observed phenotypes that are indicative of tumor cell colony. Ongoing work aim to further validate the CTC cultures using genomic sequencing and RNAse CONCLUSION: We showed decellularizd organ technology can be utilized to generate CTC cultures. Citation Format: Nikhila Reddy Sultanpuram, Isaiah Kim, Hossein Sendi, Nicole Kanpe, Tilden Hagen, Kyle Wagner, Andrew Wang. Culture of circulating tumor cells isolated from cancer patients with metastatic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 281.
Abstract 1263: Comprehensive genomic profiling to identify biomarkers predictive of response to immunotherapy
Authors: Pawan Noel, David W. Hall, Sameer S. Udhane, Min Wang, Fadel S. Alyaqoub, Szabolcs Szelinger, Audrey A. Ozols, Janine R. LoBello, Frederick L. Baehner, Gargi D. Basu
Journal: Cancer Research (2022)

Abstract Background: Immune-oncology (I-O) drugs show promise across multiple tumor types, and several biomarkers (BM) predict responsiveness to I-O therapy. In this descriptive study of clinical lab experience (2018-2021), we investigated the prevalence of genomic BMs associated with sensitivity and resistance to I-O drugs across solid tumors. Methods: The GEM ExTra® assay was used to exome-sequence 2,359 paired samples at 180X and 400X coverage for germline and tumor DNA respectively. Reportable alterations were single base substitutions, indels, copy number alterations, fusions, alternate transcripts, as well as tumor mutational burden (TMB) and microsatellite instability (MSI) status. For I-O sensitive BMs we recorded MSI-High status, TMB-High (&amp;gt; 10 mut/Mb) status, and mutations in POLE/POLD1, MLH1, MSH2/3/6, PMS1/2, PD-L1/-L2, CTLA4, CD28, ARID2, and PBRM1. For I-O resistance BMs, IDO1 amplification and mutations in B2M, JAK1/2, IDO1, KRAS and STK11 were tallied. Results: I-O sensitive BMs varied from 0% to 58% (results in Table 1 for selected tumor types). Overall, TMB-High was in 6% of samples and MSI-High in 3%; all MSI-High were also TMB-High. In the 46% of renal cell carcinoma samples with I-O-sensitive BMs, PBRM1 mutation was common (94%). In 3 TMB-High endometrial samples, POLE/POLD1 was mutated, indicative of an ultra-mutated phenotype. Of note, 35% of colorectal cancer and 8% of melanoma samples with I-O sensitive mutations also had loss-of-function mutations in JAK1/2 and B2M, suggestive of I-O resistance. In non-small cell lung cancer, co-mutation of STK11 and KRAS, suggesting inferior response to I-O therapy, was present in 4% of samples with I-O BMs. IDO1 amplification was present in less than 1% of entire cohort. Conclusions: Our study found I-O sensitive BMs in common and in rare aggressive cancers. The GEM ExTra assay can stratify cancer patients for likely responsiveness to immunotherapy. Table 1. Immune-oncology sensitive biomarkers observed across select tumors Solid tumor type % of samples with signature All (n = 2,360) 13% Melanoma (n = 50) 54% Other skin cancers (n = 13) 62% Renal cell carcinoma (n = 200) 46% Urothelial (n = 86) 22% Endometrial (n = 88) 20% Gastro-intestinal (n = 360) 12% Sarcoma (n = 90) 11% Prostate (n = 151) 6% Lung (n = 100) 4% Breast (n = 297) 2% Central nervous system (n = 60) 0% Citation Format: Pawan Noel, David W. Hall, Sameer S. Udhane, Min Wang, Fadel S. Alyaqoub, Szabolcs Szelinger, Audrey A. Ozols, Janine R. LoBello, Frederick L. Baehner, Gargi D. Basu. Comprehensive genomic profiling to identify biomarkers predictive of response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1263.
Abstract 4227: NL-201, a <i>de novo</i> agonist of IL-2 and IL-15 receptors, demonstrates antitumor activity in preclinical B cell lymphoma models
Authors: Justin Huard, Christie Mortales, Alex Chen, Ryan Swanson, Carl Walkey, Bill Arthur
Journal: Cancer Research (2022)

Abstract NL-201 is a computationally-designed IL-2/IL-15 cytokine mimetic under investigation in a phase 1 clinical trial for patients with solid tumors. This de novo protein signals through the IL-2Rβ/ɣ complex in an IL-2Rα-independent fashion, supporting immune function of both T cells and natural killer (NK) cells. In syngeneic tumor models of solid tumors, NL-201 demonstrates marked antitumor activity through multiple mechanisms of action, including upregulation of granzyme B in cytotoxic CD8+ T cells and NK cells. Here, we further explored the therapeutic potential of NL-201 in preclinical models of B cell malignancies. In cell-based studies, NL-201 augmented antibody-dependent cellular cytotoxicity (ADCC) of Toledo DLBCL (diffuse large B cell lymphoma) cells incubated with human NK cells and CD20 antibodies. Importantly, direct activation by NL-201 was specific to NK cells and did not impact STAT5 phosphorylation nor proliferation of the tested malignant cells. The administration of NL-201 monotherapy in mice bearing A20 B cell lymphoma syngeneic tumors yielded robust inhibition of tumor growth. Tumor xenografts from implanted Pfeiffer cells have also been evaluated to understand the activity of NL-201 in a model closely resembling DLBCL physiology. In summary, NL-201 is active as a single agent and in combination with CD20-targeted therapies in vitro, as well as demonstrating monotherapy activity in in vivo preclinical models of B cell malignancies as well as in combination with checkpoint inhibitors. The NL-201 enhancement of cytotoxicity by CD8+ T cells and NK cells supports additional exploration aimed at optimizing combinatorial approaches. These findings will inform the design of planned clinical studies with NL-201 in patients with B-cell lymphomas and other hematological malignancies. Citation Format: Justin Huard, Christie Mortales, Alex Chen, Ryan Swanson, Carl Walkey, Bill Arthur. NL-201, a de novo agonist of IL-2 and IL-15 receptors, demonstrates antitumor activity in preclinical B cell lymphoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4227.
Abstract 5786: Mitochondrial genome evolution in gliomas under therapy
Authors: Taylor E. Wade, Frederick S. Varn, Kevin C. Johnson, Roel G. Verhaak
Journal: Cancer Research (2022)

Abstract Gliomas are the most common malignant brain tumors and characterized by high recurrence rate and therapeutic resistance. Gliomas are clinically separated by mutations in isocitrate dehydrogenase (IDH) genes, but all subtypes have an altered energy metabolism. Mitochondria are essential cellular organelles that mediate many biological processes associated with tumorigenesis, such as energy metabolism and cell death, that can be impacted by mitochondrial mutations and copy number. As part of the Glioma Longitudinal AnalyiSiS consortium, we characterized mitochondrial genome evolution in response to treatment, using whole-genome sequencing data and associated RNA sequencing data from 152 paired tumor samples from 76 patients. Mitochondrial mutations are unequally distributed across the mitochondrial glioma genome, with only 4 of 13 mtDNA genes harboring a mutation across the cohort. Previous consortium analyses have investigated nuclear DNA hypermutation and changes in aneuploidy in response to chemotherapy and radiation treatment. Previous findings have identified hypermutation and copy number alterations as mechanisms of therapeutic resistance in glioma, but did not include analyses on mitochondrial DNA. Our analysis identified key differences between mitochondrial genome evolution and nuclear genome evolution. The mitochondrial mutational burden was not correlated with an increase in nuclear mutational burden. Unlike the nuclear DNA, we did not observe any samples with treatment-associated hypermutation. Mitochondrial copy number varied greatly but was increased at recurrence in IDH wild-type tumors. In tumors with a mutation in the IDH1 gene, mitochondrial copy number decreases were associated with an increase in aneuploidy score in samples that received radiation therapy. Expression analyses highlighted key differences in the active repair mechanisms between mtDNA and nuclear DNA. Our findings shed light on the variations in DNA repair mechanisms between the nucleus and the cytoplasm in glioma and lay the foundation for further analyses on the co-evolution of the mitochondrial and nuclear genomes in treatment-resistant tumors. Citation Format: Taylor E. Wade, Frederick S. Varn, Kevin C. Johnson, Roel G. Verhaak. Mitochondrial genome evolution in gliomas under therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5786.
Abstract 2273: Unsupervised clustering of multi-omics molecular layers reveals consensus molecular subtypes showing potential therapeutic opportunities for pancreatic cancer
Authors: Sung Hwan Lee, Jiyeon Park
Journal: Cancer Research (2022)

Abstract Introduction: Pancreatic cancer is a lethal disease showing dismal prognosis and therapeutic resistance. Previous molecular subtypes from genome or transcriptome did not show clinical relevance regarding precision strategy for optimal therapeutic options followed by precise patient classification. This study aims to uncover consensus molecular subtypes from cancer-specific multi-omics data showing clinically relevant therapeutic opportunities. Methods: We performed comprehensive analyses using the dataset from the cancer dependency map (DepMap) project, including cancer-specific molecular characterization with multi-omics data, genome-wide loss-of-function screening using the CRISPR-Cas9 system, and cancer drug sensitivity. The subtype-specific molecular signatures were validated in independent translational cohorts (TCGA-PAAD; n=150, ICGC-PACA-AU; n=461, ICGC-PACA-CA; n=317). Results: Integrative profiling of multi-omics molecular layers (Mutational signature, Copy number alteration, Transcriptome, MicroRNA, Chromatic profile, Proteome, and Metabolome) from pancreatic cancer cell lines (n=59) from the Cancer Cell Line Encyclopedia (CCLE) revealed a total of three cancer-specific molecular subtypes showing distinct tumor biology through all omics layer as well as clinical relevance with unique molecular dependency. Major molecular features of each subtype were reproducible in the validation cohorts. Subtype-specific molecular biomarkers, including mutational signature and metabolites, were identified. Finally, the target drug with subtype-specific genetic dependency was analyzed to provide precision strategy according to distinct subtypes’ molecular characterization. Conclusions: Integrative profiling from multi-omics molecular layers revealed precision strategies based on cancer-specific molecular subtypes of pancreatic cancer in terms of tumor classification and discriminative therapeutic opportunities. Prospective translational studies companion with clinical trials based on cancer-specific molecular subtypes is mandatory to establish the precision strategy for managing pancreatic cancer. Citation Format: Sung Hwan Lee, Jiyeon Park. Unsupervised clustering of multi-omics molecular layers reveals consensus molecular subtypes showing potential therapeutic opportunities for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2273.
Abstract 6189: Development of an anti hepatocellular carcinoma CAR T strategy targeting PDL1
Authors: Kyung-Sik Lee, Hye-Seong Park, Guk-Yeol Park, Gi-Chan Lee, Eun-Ji Choi, Jae-in Yu, Seung-Joo Yang, Mihwa Kim, Yoonjoo Choi, Je-Jung Lee, Joon Haeng Rhee, Bum Chan Park, Jae Eun Park
Journal: Cancer Research (2022)

Abstract [Purpose] Immunosuppressive tumor microenvironment (TME) is the major hurdle to cancer immunotherapy. Advanced hepatocellular carcinoma (aHCC) is one of the representative cold tumors with immunosuppressive TME and presents obvious correlation between immune check point expression, such as programmed cell death ligand 1 (PD-L1), and poorer prognosis. In aHCC patients, cancer cells and stellate cells in TME appeared to express high level of PD-L1, which should suppress activities of antitumor immune cells. In this context, the combination of PD-1/PD-L1 inhibitors and other therapeutic modalities are tried to treat aHCC. The chimeric antigen receptor (CAR) T cell therapy is a potent way of eradicating cells expressing targetable antigens. Removal of PD-L1 expressing cells in the aHCC TME will improve the clinical outcomes of current therapies against aHCC. In the present study, we developed an autologous anti-PD-L1 CAR T strategy and show high efficacy of tumor suppression using an HCC xenograft model. [Result] We constructed second generation CAR lentiviral vector expressing an unique anti-PD-L1 scFv manifesting moderated affinity. The scFv was specifically generated by phage display technique using human B cell-derived naïve cDNA library, which targets PD-L1 with intermediate affinity in solid tumor TME. As the secondary signaling motif, CD28 was chosen and tested along with CD3 zeta chain. The effector CAR T, named VPC1, cells specifically recognized PD-L1 expressing HCC cells and exhibited rapid and robust cytotoxic activity in 2D and 3D culture experiments. In an HCC xenograft NSG mouse model, VPC1 CAR T cells significantly suppressed the tumor growth. More importantly, VPC-1-treated animals have well tolerated the CAR T therapy with no significant adverse manifestations during one month observation period and exhibited gradual weight gains since 3 days after CAR T cell injection. [Conclusion] We hereby report that a new autologous PD-L1 CAR-T therapeutic is capable of eradicating solid tumors expressing PD-L1, which would significantly potentiate efficacies of current conventional and immunotherapeutic strategies. Citation Format: Kyung-Sik Lee, Hye-Seong Park, Guk-Yeol Park, Gi-Chan Lee, Eun-Ji Choi, Jae-in Yu, Seung-Joo Yang, Mihwa Kim, Yoonjoo Choi, Je-Jung Lee, Joon Haeng Rhee, Bum Chan Park, Jae Eun Park. Development of an anti hepatocellular carcinoma CAR T strategy targeting PDL1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6189.